Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.

代谢重编程是癌症的标志。然而，新陈代谢如何影响癌症进展尚不清楚。我们发现代谢酶酰基辅酶 A 氧化酶 1 (ACOX1) 通过调节棕榈酸 (PA) 重编程来抑制结直肠癌 (CRC) 的进展。ACOX1 在 CRC 中高度下调，这预示着 CRC 患者的临床结果不佳。功能上，ACOX1耗竭促进体外 CRC 细胞增殖和小鼠模型中的结直肠肿瘤发生，而 ACOX1 过表达抑制患者来源的异种移植物生长。从机制上讲，DUSP14 在丝氨酸 26 处使 ACOX1 去磷酸化，促进其多聚泛素化和蛋白酶体降解，从而导致 ACOX1 底物 PA 增加。累积的 PA 促进 β-连环蛋白半胱氨酸 466 棕榈酰化，从而抑制 CK1 和 GSK3 定向的 β-连环蛋白磷酸化和随后的 β-Trcp 介导的蛋白酶体降解。作为回报，稳定的 β-catenin 直接抑制ACOX1转录并间接激活DUSP14通过上调 c-Myc 进行转录，c-Myc 是 β- 连环蛋白的典型靶标。最后，我们证实 DUSP14-ACOX1-PA-β-catenin 轴在临床 CRC 样本中失调。总之，这些结果将 ACOX1 鉴定为肿瘤抑制因子，其下调会增加 PA 介导的 β-连环蛋白棕榈酰化和稳定化，并过度激活 β-连环蛋白信号传导，从而促进 CRC 进展。特别是，通过 2-溴棕榈酸酯 (2-BP) 靶向 β-catenin 棕榈酰化可以有效抑制体内 β-catenin 依赖性肿瘤生长，而 Nu-7441 对 DUSP14-ACOX1-β-catenin 轴的药理学抑制降低了 CRC 的生存能力细胞。我们的结果揭示了由 ACOX1 去磷酸化诱导的 PA 重编程在激活 β-连环蛋白信号传导和促进癌症进展中的意想不到的作用，